Abstract：
Ferroptosis and apoptosis are two types of regulated cell death that are closely associated with the pathophysiological processes of many diseases. The significance of ferroptosis-apoptosis crosstalk in cell fate determination has been reported, but the underlying molecular mechanisms are poorly understood. Herein mitochondria-mediated molecular crosstalk is explored. Based on a comprehensive spectroscopic investigation and mass spectrometry, cytochrome c-involved Fenton-like reactions and lipid peroxidation are revealed. More importantly, cytochrome c is found to induce ROS-independent and cardiolipin-specific lipid peroxidation depending on its redox state. In situ Raman spectroscopy unveiled that erastin can interrupt membrane permeability, specifically through cardiolipin, facilitating cytochrome c release from the mitochondria. Details of the erastin-cardiolipin interaction are determined using molecular dynamics simulations. This study provides novel insights into how molecular crosstalk occurs around mitochondrial membranes to trigger ferroptosis and apoptosis, with significant implications for the rational design of mitochondria-targeted cell death reducers in cancer therapy.
摘要：
铁凋亡和细胞凋亡是两种类型的调节性细胞死亡，与许多疾病的病理生理过程密切相关。已经报道了铁凋亡-凋亡串扰在细胞命运确定中的意义，但是对潜在的分子机制知之甚少。本文探讨了线粒体介导的分子串扰。基于全面的光谱调查和质谱，揭示了细胞色素c参与的Fenton样反应和脂质过氧化。更重要的是,发现细胞色素c根据其氧化还原状态诱导ROS非依赖性和心磷脂特异性脂质过氧化。原位拉曼光谱揭示了erastin可以中断膜的渗透性，特别是通过心磷脂，促进细胞色素c从线粒体释放。使用分子动力学模拟确定擦除素-心磷脂相互作用的细节。这项研究提供了关于线粒体膜周围分子串扰如何引发铁凋亡和凋亡的新见解。对癌症治疗中线粒体靶向细胞死亡减少剂的合理设计具有重要意义。
